Microbial Copper-binding Siderophores at the Host-Pathogen Interface

Abstract

Numerous pathogenic microorganisms secrete small molecule chelators called siderophores defined by their ability to bind extracellular ferric iron, making it bioavailable to microbes. Recently, a siderophore produced by uropathogenic Escherichia coli, yersiniabactin, was found to also bind copper ions during human infections. The ability of yersiniabactin to protect E. coli from copper toxicity and redox-based phagocyte defenses distinguishes it from other E. coli siderophores. Here we compare yersiniabactin to other extracellular copper-binding molecules and review how copper-binding siderophores may confer virulence-associated gains of function during infection pathogenesis. SiderophoresSiderophores (Greek for iron carrier) are a diverse group of specialized ferric iron(III)-binding metabolites that function to supply iron to the microbe and are the subject of classic works in microbial metabolism (1-3). Iron is an essential metal for most bacteria, acting as an essential cofactor in diverse physiological processes including respiration, deoxynucleotide biosynthesis, and DNA replication (4). The evolution of siderophores is viewed as a response to the appearance of O 2 in the early atmosphere, which resulted in oxidation of soluble ferrous iron (Fe(II)) to its relatively insoluble ferric form (Fe(III)) (5).Siderophores are widely synthesized among microbes, with over 500 different siderophores described. These specialized metabolites use a chemically diverse array of metal-binding prosthetic groups, often deployed in varying combinations within a single siderophore. Bacterial siderophore biosynthesis and transporter proteins are translated when intracellular iron is low, classically following transcriptional derepression by the global iron regulator, Fur (ferric uptake repressor) (6, 7). Siderophore biosynthetic pathways can be classified as non-ribosomalpeptidesynthetase/polyketidesynthase(NRPS/PKS) 2 -dependent or -independent systems. NRPS/PKS are large (Ͼ350 kDa for the yersiniabactin biosynthesis protein irp1 (8)) multienzyme complexes that use a wide range of cellular substrates to synthesize various metabolites including catecholate and phenolate type siderophores. Once secreted into the extracellular space, siderophores can bind oxidized metal ions with remarkably high affinities (9). Ferric siderophore complexes are subsequently recognized and internalized through siderophore-specific transport machinery in bacterial inner and outer membranes. Transport through the Gram-negative outer membrane transporters occurs through specialized proteins associated with the TonB protein complex, which transduces energy from the cytoplasmic proton motive force (3, 10, 11). Inner membrane ATP-binding cassette transporters in both Gram-negative and Gram-positive organisms transport ferric siderophore complexes, or the iron released from them, to the cytoplasm (12-16). Once ferric siderophores are internalized, their intracellular fate varies between different siderophores, with reported examples of Fe(III) reduction ...

Siderophores for molecular imaging applications

“…Nevertheless, there are evidences that siderophores can chelate also other metals with physiological relevance, e.g. the siderophore yersiniabactin was recently found to sequester extracellular copper to protect uropathogenic Escherichia coli from copper toxicity during human infection [19], while some siderophores appear to be involved in uptake of various non-iron metals such as yersiniabactin in zinc uptake by Yersina pestis [20,21]. Due to the indispensability of siderophore-mediated iron acquisition, this system is hijacked during microbial competition, e.g.…”

Bacterial copper storage proteins

“…As mentioned in the introduction, and covered in previous Minireviews in this Series, the interplay between Cu homeostasis systems in a pathogen and host is emerging as important for virulence (30)(31)(32)(33)(34)91). Compared to nutritional immunity used to withhold other essential metal ions, hosts are thought to expose invading pathogens to Cu (32,33,91).…”

“…In mammalian hosts ATP7A pumps Cu into the phagolysosomal compartment and Cu homeostasis systems can protect the pathogen against this attack (30)(31)(32)(33)(91)(92)(93). A number of possible defence approaches have been identified, such as Cu efflux and sequestration, including by a Cu(II)-binding siderophore (34,94). Csps are present in pathogenic bacteria including N. gonorhoeae (Csp1), Streptococcus pneumoniae (Csp3), Salmonella enterica sv.…”

Introduction: Metals in Biology

“…Our fourth Minireview, by Koh and Henderson, also deals with Cu and infection (13). Siderophores have long been known in microorganisms, mainly characterized by Fe binding.…”